ObjectiveTo investigate the molecular mechanism by which the Bushen Kaixuan Tongluo prescription exerts a renal protective effect in mice with diabetic kidney disease （DKD） by regulating the cyclic adenosine monophosphate （cAMP） signaling pathway. MethodsThirty specific pathogen-free （SPF） male db/db mice were adaptively fed for three weeks. Mice with a random tail vein blood glucose level ≥ 11.1 mmol·L^-1 and urinary albumin-creatinine ratio （ACR） ≥ 30 mg·g^-1 were considered successfully modeled. The successfully modeled mice were randomly divided into five groups with six mice in each group： the model group， the low-， medium-， and high-dose Bushen Kaixuan Tongluo prescription groups （administered at doses of 7， 14， 28 g·kg^-1·d^-1 respectively）， and the positive drug irbesartan group （administered at a dose of 20 mg·kg^-1·d^-1）. Additionally， six db/m mice were selected as the blank group. Mice in each group were given intragastric administration of the Bushen Kaixuan Tongluo prescription at the corresponding concentrations， irbesartan， or an equal volume of pure water， and the intervention lasted for 12 weeks. During the experiment， the general conditions， body weight changes， and renal function indicators of the mice were dynamically monitored. After the intervention， a blood glucose meter was used to measure the fasting blood glucose （FBG） of the mice. An automatic biochemical analyzer was employed to detect the levels of serum creatinine （SCr）， blood urea nitrogen （BUN）， urinary microalbumin （uALB）， ACR， aspartate aminotransferase （AST）， alanine aminotransferase （ALT）， total cholesterol （TC）， triglycerides （TG）， leptin （LEP）， glycosylated serum protein （GSP）， and insulin （INS） in the mice. Renal tissues were collected for hematoxylin-eosin （HE） staining， periodic acid-Schiff （PAS） staining， and Masson's trichrome staining to observe the histopathological changes. Immunohistochemistry （IHC） was used to detect the expressions of protein kinase A （PKA） and cAMP response element-binding protein （CREB） in the mice. Western blot analysis was performed to determine the expression levels of PKA， phosphorylated protein kinase A （p-PKA）， CREB， phosphorylated cAMP response element-binding protein （p-CREB）， and B-cell lymphoma-2 （Bcl-2） proteins in the renal tissues of the mice. Real-time quantitative polymerase chain reaction （Real-time PCR） was used to detect the mRNA expression levels of PKA， CREB， and Bcl-2 in the renal tissues of the mice. ResultsCompared with the blank group， the mice in the model group showed listlessness， decreased activity， and a significant increase in body weight （P<0.01）. Biochemical indicators revealed that the levels of BUN， uALB， ACR， AST， ALT， TC， TG， FBG， LEP， GSP， and INS were significantly increased （P<0.01）， while SCr showed an increasing trend with no statistically significant difference. Compared with the model group， the mice in the Bushen Kaixuan Tongluo prescription intervention groups had improved general conditions and a decreasing trend in body weight. Biochemical indicators showed that the levels of BUN， uALB， ACR， TC， GSP， and INS were significantly decreased （P<0.05）， while SCr， AST， ALT， TG， and LEP showed a decreasing trend with no statistically significant difference. Renal histopathological analysis showed that the model group exhibited typical DKD pathological features such as thickening of the glomerular basement membrane， expansion of the mesangial matrix， and deposition of collagen fibers in the renal tubulointerstitium， and all treatment groups could alleviate the above pathological damages. The IHC results showed that compared with the blank group， the expression levels of p-PKA and p-CREB in the renal tissues of the model group were significantly decreased （P<0.01）. Compared with the model group， the expression level of p-PKA in the medium-dose Bushen Kaixuan Tongluo prescription group was significantly increased （P<0.01）， while the expression level of p-CREB showed an increasing trend with no statistically significant difference. Western blot results showed that compared with the blank group， the expression levels of p-PKA/PKA， p-CREB/CREB， and Bcl-2 in the model group were significantly decreased （P<0.05）. Compared with the model group， the expression levels of these proteins in the medium-dose Bushen Kaixuan Tongluo prescription group were significantly increased （P<0.01）. Real-time PCR results showed that compared with the blank group， the mRNA expressions of PKA， CREB， and Bcl-2 in the model group were significantly down-regulated （P<0.05）. Compared with the model group， the mRNA expressions of these genes in the medium-dose Bushen Kaixuan Tongluo prescription group were significantly up-regulated （P<0.05）. ConclusionThe Bushen Kaixuan Tongluo prescription can improve the liver and kidney functions of db/db mice， correct lipid metabolism disorders and glucose metabolism imbalance. Its renal protective effect is associated with up-regulating the cAMP signaling pathway to improve renal fibrosis and reduce the level of oxidative stress， thereby protecting renal function.

In the context of an aging population, diabetes has emerged as a significant public health challenge.However, compared to the extensive research on target organs such as the cardiovascular, nervous, and renal systems, the impact of diabetes on the skeletal system has been underestimated.The pathological microenvironment of diabetes and systemic internal environment disorders harm bones by affecting bone density, disrupting bone microstructure, interfering with the bone mineralization process, and reducing the quality of bone collagen, which leads to the development of osteoporosis.Therefore, maintaining bone health should be an important component of comprehensive diabetes management.This review aims to provide an overview of the pathological characteristics, mechanisms, and treatment strategies for osteoporosis in both type 1 and type 2 diabetes, serving as a reference for bone health management in diabetic patients.

Objective:To investigate alterations in brain function among elderly patients with interstitial cystitis/bladder pain syndrome(IC/BPS)during the resting state.Methods:We prospectively recruited seven elderly patients with IC/BPS admitted to the Urology Department of Beijing Hospital from December 2023 to May 2024 as the experimental group, and concurrently selected twelve elderly healthy individuals as the control group.After enrollment, all participants underwent resting-state functional magnetic resonance imaging(rs-fMRI)scans.General clinical data, including age and gender, as well as standardized assessment scores from the Interstitial Cystitis Symptom Index(ICSI), Interstitial Cystitis Problem Index(ICPI), Visual Analogue Scale(VAS), Self-Rating Anxiety Scale(SAS), and Self-Rating Depression Scale(SDS), were collected.The data were processed using Matlab.This study employed a paired sample t-test to analyze the differences in gray matter volume between the two groups.The functional activities of the subjects' brains were analyzed using regional homogeneity(ReHo)and low-frequency amplitude(ALFF)algorithms.Based on the identified abnormal brain regions, further functional connectivity(FC)analysis was conducted to explore the connectivity patterns among the functional brain regions.Results:No significant differences were observed in age( t=-0.68, P=0.536)or gender( χ2=0.019, P=0.891)between the experimental group and the control group.The scores of SAS and SDS in the experimental group were significantly higher than those in the control group( P<0.001).No significant difference was observed in cerebral gray matter volume between the two subject groups.In contrast to the control group, the ALFF value of the left superior parietal lobe(MNI: x, y, z=-21, -66, 60; t=12.530 5)was elevated in elderly patients with IC/BPS, and the ReHo value of the left precuneus(MNI: x, y, z=-9, -54, 63; t=9.410 3)was also increased.Through FC analysis, it was revealed that elderly IC/BPS patients exhibited significantly lower FC values between the left superior parietal lobule and the central sulcus(MNI: x, y, z=21, 15, 3; t=-27.835 6), as well as between the left anterior cingulate and the left posterior cingulate gyrus(MNI: x, y, z=-12, 0, 42; t=-8.738 9)in comparison with the control group. Conclusions:In contrast to normal individuals, elderly IC/BPS patients demonstrate functional aberrations in the left superior parietal lobule and the left precuneus.Moreover, a decrease in functional connectivity is observed between the left superior parietal lobule and the central sulcus, as well as between the left precuneus and the left posterior cingulate gyrus.These abnormal functional alterations in the brain may be implicated in the maintenance and development of symptoms in IC/BPS patients.This study conducted research from the perspective of central nervous system regulation, presenting possible directions for further exploration of the pathophysiological mechanisms of IC/BPS.

In the context of an aging population, diabetes has emerged as a significant public health challenge.However, compared to the extensive research on target organs such as the cardiovascular, nervous, and renal systems, the impact of diabetes on the skeletal system has been underestimated.The pathological microenvironment of diabetes and systemic internal environment disorders harm bones by affecting bone density, disrupting bone microstructure, interfering with the bone mineralization process, and reducing the quality of bone collagen, which leads to the development of osteoporosis.Therefore, maintaining bone health should be an important component of comprehensive diabetes management.This review aims to provide an overview of the pathological characteristics, mechanisms, and treatment strategies for osteoporosis in both type 1 and type 2 diabetes, serving as a reference for bone health management in diabetic patients.

Objective:To investigate alterations in brain function among elderly patients with interstitial cystitis/bladder pain syndrome(IC/BPS)during the resting state.Methods:We prospectively recruited seven elderly patients with IC/BPS admitted to the Urology Department of Beijing Hospital from December 2023 to May 2024 as the experimental group, and concurrently selected twelve elderly healthy individuals as the control group.After enrollment, all participants underwent resting-state functional magnetic resonance imaging(rs-fMRI)scans.General clinical data, including age and gender, as well as standardized assessment scores from the Interstitial Cystitis Symptom Index(ICSI), Interstitial Cystitis Problem Index(ICPI), Visual Analogue Scale(VAS), Self-Rating Anxiety Scale(SAS), and Self-Rating Depression Scale(SDS), were collected.The data were processed using Matlab.This study employed a paired sample t-test to analyze the differences in gray matter volume between the two groups.The functional activities of the subjects' brains were analyzed using regional homogeneity(ReHo)and low-frequency amplitude(ALFF)algorithms.Based on the identified abnormal brain regions, further functional connectivity(FC)analysis was conducted to explore the connectivity patterns among the functional brain regions.Results:No significant differences were observed in age( t=-0.68, P=0.536)or gender( χ2=0.019, P=0.891)between the experimental group and the control group.The scores of SAS and SDS in the experimental group were significantly higher than those in the control group( P<0.001).No significant difference was observed in cerebral gray matter volume between the two subject groups.In contrast to the control group, the ALFF value of the left superior parietal lobe(MNI: x, y, z=-21, -66, 60; t=12.530 5)was elevated in elderly patients with IC/BPS, and the ReHo value of the left precuneus(MNI: x, y, z=-9, -54, 63; t=9.410 3)was also increased.Through FC analysis, it was revealed that elderly IC/BPS patients exhibited significantly lower FC values between the left superior parietal lobule and the central sulcus(MNI: x, y, z=21, 15, 3; t=-27.835 6), as well as between the left anterior cingulate and the left posterior cingulate gyrus(MNI: x, y, z=-12, 0, 42; t=-8.738 9)in comparison with the control group. Conclusions:In contrast to normal individuals, elderly IC/BPS patients demonstrate functional aberrations in the left superior parietal lobule and the left precuneus.Moreover, a decrease in functional connectivity is observed between the left superior parietal lobule and the central sulcus, as well as between the left precuneus and the left posterior cingulate gyrus.These abnormal functional alterations in the brain may be implicated in the maintenance and development of symptoms in IC/BPS patients.This study conducted research from the perspective of central nervous system regulation, presenting possible directions for further exploration of the pathophysiological mechanisms of IC/BPS.

Objective:To explore the effects of anshen jieyu decoction on hippocampal morphology and regulation of PI3K/AKT signalling pathway with hypothalamic-pituitary-adrenal axis expression in CUMS depressed rats.Methods:Rats were divided into a control group(Control),CUMS model group(CUMS),and ASJYD treatment group(CUMS+ASJYD).Rats in the CUMS and CUMS+ASJYD groups were exposed to 10 different chronic stressors to induce depressive-like behaviors.After modeling,the CUMS+ASJYD group received ASJYD via gavage.Depressive-like behaviors were assessed using the sucrose preference test and open field test.Serum levels of adrenocorticotropic hor-mone(ACTH)and corticosterone(CORT)were measured by ELISA.Hippocampal neuronal morphological changes were observed via Nissl staining,mitochondrial ultrastructure was examined using transmission electron microscopy,and hippocampal PI3K and AKT protein phosphorylation levels were detected by Western blot.Results:Compared with the Control group,the CUMS group showed significantly reduced sucrose consumption,preference rate,total travel distance in the open field,and central zone activity time(P＜0.01).Serum ACTH and CORT levels were elevated(P＜0.01),with disorganized hippocampal cell arrangement,reduced cell count,mitochondrial swelling,cristae blurring/rupture observed under electron microscopy,and decreased phosphorylation levels of PI3 K and AKT proteins(P＜0.01).After ASJYD treatment,the CUMS+ASJYD group exhibited significant improvements in sucrose consumption,preference rate,locomotor activity,and central zone exploration(P＜0.01),accompanied by reduced ACTH/CORT expression,alleviated hippocampal pathology,restored mitochondrial integrity with clear cristae,and increased PI3K/AKT phosphorylation(P＜0.01).Conclusion:Anshen Jieyu decoction significantly improved the depression-like be-haviour of CUMS rats,which may be achieved by down-regulating the hyperactive hypothalamic-pituitary-adrenal axis,regulating the expression of PI3K/AKT signaling pathway,and ameliorating the damage to hippocampal neurons and mi-tochondria.

Objective:To explore the effects of anshen jieyu decoction on hippocampal morphology and regulation of PI3K/AKT signalling pathway with hypothalamic-pituitary-adrenal axis expression in CUMS depressed rats.Methods:Rats were divided into a control group(Control),CUMS model group(CUMS),and ASJYD treatment group(CUMS+ASJYD).Rats in the CUMS and CUMS+ASJYD groups were exposed to 10 different chronic stressors to induce depressive-like behaviors.After modeling,the CUMS+ASJYD group received ASJYD via gavage.Depressive-like behaviors were assessed using the sucrose preference test and open field test.Serum levels of adrenocorticotropic hor-mone(ACTH)and corticosterone(CORT)were measured by ELISA.Hippocampal neuronal morphological changes were observed via Nissl staining,mitochondrial ultrastructure was examined using transmission electron microscopy,and hippocampal PI3K and AKT protein phosphorylation levels were detected by Western blot.Results:Compared with the Control group,the CUMS group showed significantly reduced sucrose consumption,preference rate,total travel distance in the open field,and central zone activity time(P＜0.01).Serum ACTH and CORT levels were elevated(P＜0.01),with disorganized hippocampal cell arrangement,reduced cell count,mitochondrial swelling,cristae blurring/rupture observed under electron microscopy,and decreased phosphorylation levels of PI3 K and AKT proteins(P＜0.01).After ASJYD treatment,the CUMS+ASJYD group exhibited significant improvements in sucrose consumption,preference rate,locomotor activity,and central zone exploration(P＜0.01),accompanied by reduced ACTH/CORT expression,alleviated hippocampal pathology,restored mitochondrial integrity with clear cristae,and increased PI3K/AKT phosphorylation(P＜0.01).Conclusion:Anshen Jieyu decoction significantly improved the depression-like be-haviour of CUMS rats,which may be achieved by down-regulating the hyperactive hypothalamic-pituitary-adrenal axis,regulating the expression of PI3K/AKT signaling pathway,and ameliorating the damage to hippocampal neurons and mi-tochondria.

Objective To clarify the anti-inflammatory quality markers(Q-markers)of Salvia plebeia and determine their contents,so as to provide a reference for the quality control of Salvia plebeia.Methods The main components of Salvia plebeia were characterized by high-performance liquid chromatography-quadrupole time-of-flight tandem mass spectrometry(UPLC-Q-TOF-MS/MS).According to the fragmentation information of the secondary mass spectrometry and the literature data,the analysis and identification were carried out.Further,the active components with high oral bioavailability(OB)and in line with the five principles of drug-like(DL)were screened from the identified chemical components through the SwissADME platform.The SwissTargetPrediction database was used to find and predict the component targets of Salvia plebeia.Disease targets were screened through online Mendelian Inheritance in Man(OMIM),GeneCards database,etc.String11.5 database and Cytoscape3.7.2 software were used to construct the PPI network and screen core targets.Gene Ontology(GO)annotation and KEGG pathway enrichment analysis were performed using DAVID6.8,and the enriched pathways were verified by experiments to clarify their mechanism of action.Reverse traceability was used to analyze the potential pharmacodynamic material basis of key pathways,experimental verification was carried out,and high-performance liquid chromatography(HPLC)content determination method was established.Results 36 main components were identified,including flavonoids and terpenoids.Further screening of 190 active ingredients and disease intersection targets;through network topology screening,18 core targets were obtained;enrichment analysis showed that the primary pathways involved in the anti-inflammatory effect of Salvia plebeia include:NF-κB signaling pathway,PI3K-Akt signaling pathway and TNF signaling pathway.Four related components including homoplantaginin,hispidulin,luteolin and isorhamnetin were obtained by reverse traceability of the NF-κB signaling pathway.Molecular docking demonstrated excellent docking activities of the 4 components to PTGS2 with the binding energies of-9.5,-9.7,-9.4,and-9.4 kcal·mol-1,respectively.According to the measurability of quality markers,it was determined that homoplantaginin and hispidulin could be used as anti-inflammatory quality markers of Salvia plebeia.Western Blot results showed that homoplantaginin and hispidulin could significantly reduce the expression of COX-2 and NF-κB p-p65(P<0.05,P<0.01).Conclusion The anti-inflammatory quality markers of Salvia plebeia are homoplantaginin and hispidulin,which can exert anti-inflammatory effects through the NF-κB pathway.

Objective:To screen the interacting protein of ubiquitin-conjugating enzyme E2S(UBE2S)and construct the hepatocellular carcinoma(HCC)based on UBE2S interacting protein prognosis model(UIPM),and to discuss the value of UIPM in assessing the prognosis of the HCC patients.Methods:Co-immunoprecipitation(Co-IP)was used to screen the protein complexes binding to Flag-UBE2S.After validation by sodium dodecyl sulphate-polyacrylamide gel electrophoresis(SDS-PAGE)and Western blotting methods;liquid chromatography-mass spectrometer(LC-MS)was used to identify the UBE2S interacting proteins;Gene Ontology(GO)functional enrichment analysis and Kyoto Encyclopedia of Genes and Genomes(KEGG)signaling pathway enrichment analysis were conducted on these proteins;the prognosis-related proteins from The Cancer Genome Atlas(TCGA)were cross-referenced with UBE2S interacting proteins by survival package of R software;the key proteins were extracted through LASSO regression analysis to build the UIPM;the prognostic model risk scoring formula was established.The HCC patients in TCGA were divided into high risk group and low risk group based on median value of the risk scores.The predictive accuracy of UIPM was evaluated by receiver operating characteristic curve(ROC),and the predictive accuracy was further validated by International Cancer Genome Consortium(ICGC)Database;univariate regression analysis and multivariate Cox regression analysis were used to detect whether the UIPM risk score was an independent prognostic factor for HCC.Furthermore,the nomogram model was built.Results:A total of 97 UBE2S interacting proteins were identified through Co-IP combined with LC-MS analysis.The GO functional enrichment analysis and KEGG signaling pathway enrichment analysis results showed that the interacting proteins were closely associated with cysteine-type endopeptidase activity,oxidative stress,and cell death.The TCGA revealed 5 163 HCC prognosis-related proteins;after intersecting with UBE2S interacting proteins,40 prognosis-related interacting proteins were found.Seven key proteins were determined through LASSO regression analysis,including UBE2S,heat shock protein family A member 8(HSPA8),heterogeneous nuclear ribonucleoprotein H1(HNRNPH1),chaperonin containing TCP1 subunit 3(CCT3),eukaryotic translation initiation factor 2 subunit 1(EIF2S1),receptor for activated C kinase 1(RACK1),and actin related protein 2/3 complex subunit 4(ARPC4),and the UIPM was constructed.There was significant difference in survival rate of the patients between high risk group and low risk group(P<0.05).The ROC curve analysis results showed the area under ROC curve(AUC)values of UIPM for predicting 1-year,2-year,and 3-year survival risk scores of the HCC patients were all greater than 0.7,indicating the model had high predictive accuracy.This was also confirmed by ICGC Database data.The univariate and multivariate Cox regression analysis results showed that the UIPM risk score was an independent prognostic risk factor for the HCC patients(P<0.05).The nomogram results showed good consistency between predicted survival rate and actual survival rate of the patient.Conclusion:A total of 97 interacting proteins that interact with UBE2S may promote the occurence and devolopment of HCC through oxidative stress and dysregulation of ferroptosis pathways.The UIPM risk score is an independent risk factor for the prognosis of HCC and can be used to predict the outcomes of the patients.UBE2S,HSPA8,HNRNPH1,CCT3,EIF2S1,RACK1,and ARPC4 could be regarded as the new biomarkers and therapeutic targets for HCC.

Neutrophils originate from the bone marrow,differentiating from hematopoietic stem cells,and are the most prevalent polymorphonuclear leukocytes in the blood,accounting for approximately 70%of the total white blood cells in adult peripheral blood.Neutrophils are recognized as one of the relatively short-lived cells in the body,with a normal half-life of just a few hours in the peripheral blood,which rely on continuous replenishment from the bone marrow to maintain the number.As short-lived effectors of the innate immune system,neutrophils participate in various inflammatory and immune processes,and constitute the first line of defense against infection,playing a crucial role in the activation and regulation of both innate and adaptive immunity.Neutrophils were once considered as key effectors of inflammation and infection.Because of their short lifespan and non-proliferative nature,the role of neutrophils in cancer was overlooked.Their role in cancer has been increasingly recognized in recent years.However,more and more studies demonstrate that neutrophils play a much more significant role in cancer than previously thought.Breast cancer is one of the common malignant tumors in women,and its morbidity and mortality are in the forefront of female malignant tumors.The incidence of breast cancer is rising globally,posing a severe threat to the physical and mental health of women worldwide.Recent studies confirm that tumor-associated neutrophils(TANs)have become a critical component of the tumor microenvironment(TME)and play a significant role in the development,progression and metastasis of breast cancer.TANs are formed via the interaction of various tumor-derived cytokines which stimulate and recruit neutrophils to accumulate in the TME.The strong plasticity and diversity of neutrophils endow TANs with dual potential to both promote and inhibit tumors.TANs advance breast cancer progression by promoting tumor growth and metastasis,supporting tumor angiogenesis,immune suppression,and generating neutrophil extracellular traps(NETs).Conversely,TANs mediate antitumor responses through direct tumor cell killing and contributing to the formation of antitumor immune network.Research on TANs-related breast cancer therapies,particularly in triple-negative breast cancer(TNBC),has become a research hotspot.This review summarized recent advances in the origin,formation,classification and function of TANs in breast cancer,as well as a detailed discussion of their clinical relevance.We further combined recent clinical studies to systematically summarize the treatment strategies targeting TANs in breast cancer,with the aim of providing new insights into the functional mechanisms of TANs and the treatment of breast cancer.